PROJECT SUMMARY Molecular, cellular and circuit mechanisms for memory-linking deficits in psychiatric disorders Source and relational memory problems are commonly associated with a number of psychiatric conditions, including schizophrenia [1, 2], and major depression [3]. A key component of these complex cognitive problems is the inability to properly link information about items and events acquired at different times. Unfortunately, very little is known about how the brain routinely links and integrates information across time. Additionally, abnormal levels of Chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES), a ligand for the C-C chemokine receptor type 5 (CCR5), have been found in association with major depression [4], and schizophrenia[5], but it is unclear whether and how changes in this cytokine signaling system affects the complex cognitive phenotypes associated with these disorders. Recent studies in our laboratory revealed that CCR5 in neurons negatively regulates MAPK/CREB signaling, and that this modulates not only memory formation[6], but also how memories are linked across time, a mechanism that could contribute to source and relational memory problems in schizophrenia [1, 2], and major depression [3]. Results from recent studies, including those from our laboratory [7-18], suggest that learning triggers CREB activation and a subsequent temporary increase in neuronal excitability[19-21], that for a time biases the allocation of a subsequent memory to the neuronal ensemble encoding the first memory. We just reported that the resulting overlap between neuronal ensembles encoding both memories could link these memories across time, such that the recall of one memory leads to the recall of the other [22]. Here, we propose to use state-of-the-art tools, such as a new generation of head-mounted fluorescent microscopes developed in our lab, TetTag mice, a new optogenetic tool, and chemogenetics, to test the novel hypothesis that a) the opposing roles of CCL5/CCR5 and CREB signaling modulate neuronal excitability in CA1 (Aim 1), b) and consequently memory allocation in this structure (Aim 2), c) that memory allocation mechanisms determine the overlap between neuronal ensembles encoding distinct memories (Aim 2), and therefore, d) supports memory linking across time (Aim 3). Importantly, the highly mechanistic experiments proposed here will also include an FDA approved drug known to inhibit CCR5, and that could be used to help treat possible memory linking problems caused by deregulation of CCR5 in psychiatric conditions. These studies will focus on CA1 since this structure has been implicated in human relational memory[23], and the hippocampus is involved in cognitive deficits associated with schizophrenia [1, 24], and major depression [25]. Thus, the studies proposed will not only further our understanding of how memory allocation affects memory linking across time, a novel concept in memory research, they will address a possible neuroinflammatory mechanism[26] that could contribute to source and relational memory problems.